The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
There are many conditions that affect the eye. Some common conditions, for example, include aqueous deficiency and evaporative dry eye syndrome (DES), corneal ectasia, corneal limbal stem cell deficiency, keratoplasty graft rejection episode and failure, and Fuchs' dystrophy. However, conditions such as these are difficult to diagnose and treat.
Dry Eye Syndrome: Dry eye syndrome (DES) is a worldwide public health problem. In the United States alone, an estimated 25 million patients suffer from DES. DES adversely affects vision and causes constant symptoms of dryness, eye irritation, and foreign body sensation and thus negatively impacts patients' quality of life. Severe DES can lead to corneal melting compromising the integrity of the eye and can cause blindness. DES can be classified into aqueous deficiency DES or evaporative DES. In aqueous deficiency DES, there is deficiency in the quantity of tears secreted by the lacrimal glands. Whereas, in evaporative dry eye, which is caused by meibomian gland dysfunction (MGD), the problem lies in deficiency in the lipid layer of the tear film leading to excessive evaporation of the tears. The diagnosis and treatment of DES has become a challenge. Major research is directed at finding new remedies for DES but those efforts are limited by the fact that there is no gold standard for the diagnosis of DES. Available diagnostic tests lack standardization and usually are not representative of patient symptoms, in addition to other limitations.
The medical literature has shown poor association between current dry eye test and patient symptoms. Additionally, the current tests are poorly standardized tests as they are affected by factors that are difficult to control. For example, tear breakup time is affected by temperature and humidity of the examination room. Moreover, reflex lacrimation as the patient keeps his or her eyes open to obtain measurements can invalidate obtained measurements. The Schirmer test (in which paper strips are inserted into the eye to measure moisture production) is invasive and unpleasant to the patient. Further, hanging filter paper from a patient's eyes could result in reflex tearing that can affect obtained measurements. Fluorescein or other vital stains of the ocular surface are examples of tests that detect the injurious effect of DES on the ocular surface epithelium; however, results of those tests are identified using a slit lamp with magnification of only up to 16×. Such accuracy might be enough to diagnose moderate to severe dry eye, but certainly would not be enough to detect mild cases or monitor response to treatment. Indeed, the discrepancy between signs and symptoms of dry eye patients most likely stems from a lack of accuracy. Corneal nerves are sensitive enough to detect microscopic injuries to the ocular surface, but the available tests are not sensitive enough to visualize that injury or quantify it. Another limitation of current clinical techniques is that many are subjectively evaluated. What an examiner would consider mild corneal and conjunctival fluorescein staining, another could consider moderate and vice versa.
Diagnostic modalities have been recently introduced such as confocal microscopy and tear film osmolarity. Using confocal microscopy to diagnose DES is a time-consuming procedure that requires contact with the ocular surface and that makes it difficult to incorporate into everyday clinics and limits its use to research. Furthermore, it can only capture images over a small area of the total cornea. Tear film osmolarity has shown promise as a quantitative method to diagnose DES, but it is also invasive and time consuming. The literature has also shown lack of a cut off tear osmolarity values and a great overlap between normal subjects and DES patients. Until enough data proves otherwise, lubricating a dry eye would be able to improve the health of the ocular surface by providing an alternative to the inadequate natural tears, but does not alter the tear film osmolarity. Thus, looking at the osmolarity might not provide an insight about the response of the patient to treatment.
Corneal ectasia is a progressive disease that adversely affects the structural integrity of the cornea. The weakened cornea bulges, and crippling irregular astigmatism starts to develop. The astigmatism degrades vision and as the disease progresses, scarring of the cornea occurs. Corneal ectasia includes keratoconus, pellucid marginal degeneration, post-refractive surgery ectasia, and other rare diseases such as keratoglobus. Modalities for the treatment of corneal ectasia have been developed, such as corneal collagen cross-linkage that uses ultraviolet (UV) light and Riboflavin to stiffen the cornea and halt the progression of the disease. It is desirable to halt the progression of the disease at a very early stage, before vision is degraded by irregular astigmatism or scarring. Therefore, there is a need for a specific and sensitive sign that can detect those early patients to allow treatment before irreversible corneal damage occurs.
Post-refractive surgery ectasia is a devastating complication of refractive surgery, an elective procedure received by millions of patients in the United States alone. The most common cause of this complication that threatens vision in those patients is performing the refractive surgery on an early ectasia patient who was not detected by the conventional current diagnostic techniques. This highlights the need for a specific and sensitive sign that can be used to detect those early patients to save them from such a devastating complication.
Corneal topography and thickness are among the current diagnostic criteria of ectasia. Their use is complicated by their variations among the general populations. Normal range of corneal thicknesses is wide, and overlapping between normal thin corneas and early ectasia patients complicates the use of this criterion in the diagnosis of early cases of ectasia. Thus, lack of specificity is a significant limitation of using corneal thickening for the diagnosis of the ectasia. Corneal topography use in diagnosis of ectasia shares the same limitations as corneal thinning Irregular astigmatism is seen in normal subjects and in ectasia patients complicating its use to make the diagnosis, especially in mild cases.
Keratoplasty Graft Rejection/Failure and Fuchs' Dystrophy: Keratoplasty, or corneal transplantation, is used to replace a damaged or diseased cornea with a donated corneal tissue graft. About 60,000 corneal transplants are performed every year in the United States alone, it is not uncommon for a graft recipient's body to reject the donated corneal tissue. In fact, it is estimated that 50% of those patients will experience at least one episode of rejection, and 20% of transplants will ultimately fail by the third year, commonly due to the patient's immune system attacking the graft endothelium and destroying it. To preserve the graft and prolong its survival, rejection must be detected and reversed as early as possible. Unfortunately, however, the early stages of rejection are not easily identified. Currently, methods such as slit-lamp examination are used to detect rejection, but this method offers only limited magnification and mild subclinical rejection episodes are often missed. Further, performing endothelial cell count using specular microscopy lacks sufficient reproducibility, sensitivity, and specificity. Finally, measuring the central cornea thickness lack sufficient sensitivity to make it useful in the diagnosis of mild cases, and the wide range of normal corneal thickness complicates it use for diagnosis of mild corneal graft rejection and edema.
Fuchs' dystrophy (or Fuchs' endothelial dystrophy) is a degenerative disease of the corneal endothelium with accumulation of guttae (focal outgrowths) from the endothelial surface of the cornea. Degeneration of the corneal endothelial cells in Fuchs' dystrophy leads to corneal edema and vision loss. Although the disease is most common in people in their 50s and 60s, Fuchs' dystrophy can begin to affect people while in their 30s and 40s, so it is important to accurately identify the condition in its early stages. The same commonly used methods of detecting corneal graft rejection are often used to diagnose Fuchs' dystrophy, but these methods have the same limitations as discussed above. Additionally, there is no cut-off value that can define rejection, failure, or Fuchs' dystrophy. Similarly, using endothelial cell count is equally imprecise, as there is no cut-off value for endothelial cell count. The number of endothelial cells that can maintain a clear cornea is unknown. Further, it has been shown that reliable endothelial cell count is not possible in at least one third of Fuchs' dystrophy patients.
Fuchs' dystrophy is the leading cause of corneal transplantation in the United States, accounting for almost a quarter of all keratoplasties. About 5% of the United States population older than 40 years has Fuchs' dystrophy. This condition is an aging disease and as our population ages, the prevalence of Fuchs' dystrophy is expected to rise even more and is thus expected to impose an even more significant public health problem. Fuchs' dystrophy imposes challenge on eye banking. The confusion between normal subjects and early Fuchs' dystrophy carries the risk of either transplanting patients with early Fuchs' dystrophy corneal grafts or, on the other hand, the unnecessary wasting of corneal tissue. Further, the demand on corneal tissue is growing. The aging of the population, the increased prevalence of Fuchs' dystrophy, and the lowered threshold for endothelial keratoplasty are widening the gap between the demand and the supply. However, developing de novo corneal guttae in corneal grafts has been reported, which is most likely an effect of transplanting undiagnosed Fuchs' dystrophy grafts.
Limbal stem cell deficiency of the cornea is another concern. Limbal stem cells are responsible for repopulating the corneal epithelium. Deficiency in the stem cell of the cornea leads to failure of the epithelium to renew or repair itself. This results in epithelial defects of the cornea that is persistent and resistant to treatment and loss of the corneal clarity leading to blindness. The basal epithelial layer of the cornea is the innermost layer of epithelial cells that is produced by those stem cells and is a precursor of the more superficial layers of the corneal epithelium. The diagnosis of limbal stem cell deficiency (LSCD) is currently done using the slit lamp which uses up to a magnification of only 16× and is unable to visualize the limbal stem cells nor the basal epithelial layer. Confocal microscopy is able to visualize the basal layer of the epithelium but through a very small window (0.4 mm×0.4 mm) and that is not representative of the cornea as a whole. It is also not possible to construct cross-sectional view of those cell layers.
Optical coherence tomography (OCT) is a noninvasive optical signal acquisition and processing method that captures micrometer-resolution, three-dimensional images from within, for example, biological tissue. OCT has proven to be an indispensable tool for imaging the retina and the optic nerve. It has changed the practice of ophthalmology and has become the gold standard for diagnosis and management of diseases with significant morbidity and prevalence such as age-related macular degeneration and glaucoma. Nevertheless, OCT has not yet achieved such a role in anterior segment in general and cornea imaging in particular. This is most likely due to the lack of standardized clinical applications for the device in imaging the anterior segment and cornea.
It is therefore desirable to provide improved indices for diagnosing corneal conditions such as dry eye syndrome, corneal ectasia, keratoplasty rejection and failure, and Fuchs' dystrophy. It is further desirable that these improved indices be usable with current and future imaging devices such as OCT systems, or any other imaging device or system capable of providing high-resolution images of the eye and in particular the cornea, for identifying and monitoring corneal conditions.